European Thyroid Journal最新文献

Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth and constitutes one of the most common causes of preventable intellectual disability worldwide. Central CH is caused by insufficient pituitary or hypothalamic control of thyroid function, biochemically characterized by a low serum free thyroxine (fT4), in combination with a low, normal or mildly elevated thyroid-stimulating hormone (TSH). Central CH is less common than primary CH and is part of multiple pituitary hormone deficiencies (MPHD) in most of the cases. MPHD at birth, also known as 'congenital hypopituitarism', is a potentially life-threatening condition due to the possible co-occurrence of adrenocorticotropin hormone and growth hormone deficiency that can result in severe hypoglycemia and adrenal crisis. To date, central CH is the only pituitary hormone deficiency suitable for newborn screening (NBS), providing an opportunity for early detection of MPHD. Even though the first NBS programs utilized T4-based methods that were able to identify central CH, most countries have since transitioned to TSH-based approaches due to the high rate of false positives associated with T4-based strategies. Now, 50 years after the introduction of NBS for CH, only a few countries around the world have a screening program capable of detecting central CH. In this paper, we review the past, present and future of NBS for central CH. We will outline the importance of early detection of central CH and discuss the challenges and opportunities of screening for this condition.

Objective: In the general population, women pregnant with a male fetus (MF) have a higher prevalence of gestational diabetes mellitus (GDM) compared with those pregnant with a female fetus (FF). Some studies suggest a higher prevalence of GDM in euthyroid pregnant women with thyroid autoimmunity (TAI+) compared with women without TAI (TAI-). However, whether the impact of TAI on GDM correlates with fetal gender has not been documented.

Design/methods: A single-center cohort study including 1201 women who were screened at a median of 12 (11-14) weeks of pregnancy for thyroid disorders (TSH, free T4 and thyroid peroxidase antibodies (TPOAb)) and at 24-28 weeks for GDM with an oral glucose tolerance test. Exclusion criteria were pre-pregnancy diabetes or hypertension, thyroid dysfunction (treated or untreated) before and after screening, thyroid screening after 20 weeks of pregnancy and assisted pregnancies. The diagnosis of GDM was based on the 2013 WHO criteria, and that of TAI by increased TPOAb levels (≥60 kIU/L).

Results: Overall, 622 women were expecting a FF (51.8%) and 579 a MF (48.2%). Seventy-five women were TAI+ (6.2%). The overall prevalence of GDM was 19.6%, 28% in TAI+ women and 19% in TAI- women (P = 0.008 after adjustment for confounders). In women who were expecting a FF, the prevalence of GDM was 34.4% in TAI+ women vs 19.2% in TAI- women; P = 0.002.

Conclusions: The prevalence of GDM was increased in euthyroid TAI+ women, but only in the case of pregnancies with a FF. This is opposite to the result observed in the general population and deserves more research to explore the underlying mechanisms.

Objective: To evaluate the current quality of thyroid ultrasound reports in the Community of Madrid.

Methods: Consecutive thyroid ultrasound reports from patients evaluated in the endocrine outpatient clinics of eight academic hospitals in the Community of Madrid were assessed for quality during 2021 and 2022. Descriptions of eight different features were evaluated: number and axes of dimensions, composition, echogenicity, margins, shape, calcifications and category of suspicion. Features were considered adequately reported if described for all nodules ≥1 cm. The number of correctly reported features was compared by year of data capture (2021 vs 2022), specialty of the informant (radiologist vs endocrinologist), and origin of the report (in-house vs outsourced center). The quality of reports for assessing the need for cytological evaluation and/or growth during follow-up was evaluated.

Results: A total of 1234 reports were included, 63% from 2021; 82% were issued by radiologists and 89% were issued in-house. Composition and echogenicity were the most frequently reported (79% and 72%, respectively). The rest of the features were appropriately described in less than half of the reports. Forty percent of the reports were good to select nodules for biopsy, 23% had sufficient data to assess growth during follow-up, and only 13% met both quality criteria. The overall quality of reports was worse in outsourced centers (median number of described features 2 vs 4, P < 0.001) and better when issued by endocrinologists (median number of described features 6 vs 3, P < 0.001).

Conclusions: Most thyroid ultrasound reports issued in the Community of Madrid provide insufficient data to make management decisions regarding thyroid nodules.

The development of mouse models for thyroid cancer has significantly advanced over the years, enhancing our understanding of thyroid tumorigenesis, molecular pathways and treatment responses. The earliest mouse models of thyroid cancer relied on hormone, radiation or chemical carcinogenesis to induce tumors. However, as our understanding of the genetic alterations driving thyroid cancer has expanded, more sophisticated genetic engineering techniques have been employed to create models with thyroid-specific expression of these driver mutations. While driver mutations can initiate tumorigenesis, they are often insufficient to sustain cancer progression and invasion, which significantly limits their usefulness in studying advanced thyroid cancers. Recent studies exploring the genomic landscape of advanced thyroid cancer have identified several cooperating mutations, which are secondary genetic alterations that work alongside driver mutations to promote thyroid tumor progression. Indeed, mice with a combination of oncogenic drivers and common cooperating alterations have been developed, demonstrating that these alterations function in conjunction with the oncogenic driver to promote the progression to advanced thyroid cancer. These models provide important preclinical tools to explore how cooperating alterations influence the response to therapies, particularly those targeting the oncogenic driver. This review will focus on recent publications that broaden the scope of advanced thyroid cancer models by combining thyroid-specific oncogenic driver expression with various cooperating mutations.

Thyroid hormone (TH) is essential for brain development in utero and during the first 2 to 3 years of life. The negative effects of TH deficiency on brain development are irreversible. Early detection of TH deficiency in neonates (congenital hypothyroidism (CH) through newborn screening (NBS)) allows for early treatment, thereby preventing brain damage. Screening for CH began in 1973 with the measurement of total thyroxine (T4) in dried blood spots. The enhanced sensitivity of thyroid-stimulating hormone (TSH) measurement has prompted a shift in the approach to NBS for CH. Currently, worldwide, the majority of NBS programs for CH employ TSH as the primary screening marker. However, a select few programs still utilize T4 as the primary marker, enabling the detection of both primary and central CH. This review provides an overview of the laboratory aspects of the screening on CH from the start of screening to the present.

Objective: To analyse at our institution the criteria for selecting a first-line therapy for patients with advanced radioiodine-refractory thyroid cancer and their clinical responses, safety and survival outcomes.

Patients and methods: We extracted data from 69 consecutive patients referred to Federico II University Hospital from September 2016 to September 2024, among whom 44 patients were treated with TKIs as first-line treatment and outside any clinical trial, and form the basis of this report.

Results: Thirty-one (71%) patients were treated with the antiangiogenesis inhibitor lenvatinib and 13 (29%) were treated with selective tyrosine kinase inhibitors (s-TKIs). Among the latter, eight patients were treated with dabrafenib + trametinib (DT), two patients were treated with selpercatinib because of contraindications to lenvatinib, and three patients received DT as redifferentiation therapy. A RECIST partial response was observed in 28% of patients treated with lenvatinib, in 63% of those treated with DT and in one of the two patients treated with selpercatinib. Grade ≥3 adverse events occurred in 13 (42%) patients treated with lenvatinib and only in 1 (9%) patient treated with DT. Progression-free survival (PFS) and overall survival rates at 1 year were 72% and 83% in lenvatinib-treated patients and 69% and 83% in DT-treated patients, respectively. In both selpercatinib-treated patients, the PFS at data cut-off was 10 months. No treatment-related deaths were observed.

Conclusion: S-TKIs permitted tailoring systemic treatment based on disease location, tumour volume and patient comorbidities, achieving satisfactory tolerance and outcomes in selected patients with an actionable driver mutation and with contraindications to angiogenesis inhibitors or candidates for redifferentiation therapy.

Background: In relapsing differentiated thyroid cancer (DTC), the in vivo evaluation of natrium-iodide symporter (NIS) expression is pivotal in the therapeutic planning and is achieved by 131/123Iodine (131/123I) whole body scan. However, these approaches have low sensitivity due to the low resolution of SPECT. 18F-Tetrafluoroborate (TFB) has been proposed as a viable alternative, which could outperform 131/123I scans owing to the superior PET resolution. We have reviewed the literature to collect the available data on TFB diagnostic performance and compare it with the standard methods.

Methods: Two authors searched PubMed, CENTRAL, Scopus, Web of Science and the web for studies evaluating the biodistribution and dosimetry of TFB in patients with DTC. General characteristics, technical parameters, procedures' sensitivities and standards of reference were extracted from the selected studies. The risk of bias was evaluated with the QUADAS-2 scoring system.

Results: Five studies were included in the review. Two analysed TFB's biodistribution and dosimetry, while the other three assessed its diagnostic performance. The diagnostic comparators were 18F-FDG PET/CT (all cases), 124I-PET/CT (one study) and diagnostic/therapeutic 131I-SPECT/CT (one study each). TFB performed better than 131I; the TFB and 18F-FDG PET/CT combination achieved the best sensitivity. TFB delivered significantly less dose than the other NIS tracers.

Conclusion: TFB is a promising tracer in relapsing DTC, showing higher sensitivity and less radiation exposure than the standard methods. The TFB and 18F-FDG combination appears particularly intriguing, especially when disease heterogeneity is suspected. However, data are still sparse and need to be confirmed by further investigations.

Objective: Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) cause Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with muscle hypoplasia and spastic paraplegia as key symptoms. These abnormalities have been attributed to impaired TH transport across brain barriers and into neural cells, thereby affecting brain development and function. Likewise, Mct8/Oatp1c1 (organic anion-transporting polypeptide 1c1) double knockout (M/Odko) mice, a well-established murine AHDS model, display a strongly reduced TH passage into the brain as well as locomotor abnormalities. To which extent the peripheral nervous system is affected by combined MCT8/OATP1C1 deficiency has not been addressed.

Methods: Using the sciatic nerve as a model, we studied the spatiotemporal expression of TH transporters as well as the sciatic thyroidal state, sciatic nerve myelination and function in M/Odko mice by immunofluorescence, qPCR, Western blotting and electrophysiology.

Results: We detected MCT8 protein expression in sciatic nerve axons, whereas OATP1C1 expression was observed in a subset of endothelial cells early in postnatal development. The absence of MCT8 and OATP1C1 did not alter the thyroidal state of isolated nerves at P12. Moreover, electrophysiological studies did not disclose any significant alteration in sciatic nerve signal propagation parameters in adult M/Odko mice. Although Schwann cell numbers were similar, Western blot analysis showed a mild form of hypermyelination in adult M/Odko mice.

Conclusions: Altogether, our data point to a largely unaffected sciatic nerve structure and function in the absence of MCT8 and OATP1C1.

Background: Thyroid eye disease (TED) is the most prevalent extrathyroidal manifestation of Graves' disease (GD). Emerging evidence suggests a relationship between elevated total and low-density lipoprotein (LDL) cholesterol levels and TED. This study aimed to investigate this correlation in the Brazilian population by analyzing data from two tertiary care centers.

Methods: Data were collected from GD patients treated with methimazole between 1999 and 2021, excluding those receiving other treatments. Laboratory results and information on smoking habits, statin use and medications affecting lipid profiles during the euthyroid state were analyzed.

Results: Smoking and elevated LDL cholesterol levels were significantly associated with TED activity and severity. Logistic regression revealed correlations between higher LDL cholesterol, total cholesterol and increased clinical activity score (P < 0.01, OR: 1.012, 95% CI: 1.003-1.021; P < 0.01, OR: 1.010, 95% CI: 1.002-1.018). These were also associated with more severe disease forms as defined by EUGOGO (P < 0.01, OR: 1.015, 95% CI: 1.006-1.024; P < 0.005, OR: 1.011, 95% CI: 1.004-1.019). Multiple regression confirmed that TED activity was significantly correlated with LDL cholesterol (P < 0.01) and smoking status (P < 0.01). Disease severity was associated with reduced HDL cholesterol (P < 0.05, OR: 0.973, 95% CI: 0.948-0.999), elevated LDL cholesterol (P < 0.005, OR: 1.013, 95% CI: 1.004-1.023) and active smoking (P < 0.05, OR: 2.881, 95% CI: 1.190-6.971).

Conclusion: Elevated LDL cholesterol may serve as a potential indicator of TED. Further research is needed to determine whether lipid-lowering interventions could reduce TED risk or improve its management.

Objective: Thyroid hormones control a variety of processes in the central nervous system and influence its response to different stimuli, such as ischemic stroke. Post-stroke administration of 3,3',5-triiodo-L-thyronine (T3) has been reported to substantially improve outcomes, but the optimal dosage and time window remain elusive.

Methods: Stroke was induced in mice by transient middle cerebral artery occlusion (tMCAO), and T3 was administered at different doses and time points before and after stroke.

Results: We demonstrated a dose-dependent protective effect of T3 reducing infarct volumes with an optimal T3 dosage of 25 μg/kg. In addition, we observed a time-dependent effectiveness that was most profound when T3 was administered 1 h after tMCAO (P < 0.001), with a gradual reduction in efficacy at 4.5 h (P = 0.066), and no reduction in infarct volumes when T3 was injected with an 8-h delay (P > 0.999). The protective effect of acute T3 treatment persisted for 72 h post-tMCAO (P < 0.01) and accelerated the recovery of motor function by day 3 (P < 0.05). In-depth investigations further revealed reduced cerebral edema and diminished blood-brain barrier leakage, indicated by reduced extravasation of Evans blue and diminished aquaporin-4 expression.

Conclusion: Our findings suggest that T3 may be a promising intervention for ischemic stroke in the acute phase.